title: Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model.
abstract: OBJECTIVE
  Erlotinib is used to treat non-small-cell lung cancer (NSCLC), which targets epidermal growth factor receptor (EGFR) tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR (pEGFR) levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model.
  
  
  METHODS
  Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib (4, 12.5, or 50 mg/kg). Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration. The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays.
  
  
  RESULTS
  The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC50 value of 1.80 μg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a Kbio value of 0.507 cm(3)/week, which described the impact of pEGFR degradation on tumor growth.
  
  
  CONCLUSIONS
  The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.forename: Meng-yao
authors.initials: MY
authors.lastname: Li
authors.forename: Han-qing
authors.initials: HQ
authors.lastname: Li
authors.forename: Chen-hui
authors.initials: CH
authors.lastname: Deng
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Tian-yan
authors.initials: TY
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors